The synthesis of corticosteroids having therapeutic utility, such as mometasone, betamethasone and beclomethasone, requires functionalization of the C-9 and C-11 positions of the steroid molecule. The functionality is generally introduced via .DELTA..sup.9,11 steroid intermediates.
Methods for preparing steroids having a 9,11 double bond are known in the art. For example, an 11-hydroxy steroid can be converted to the corresponding mesylate (by treating with mesyl chloride) which is transformed into a .DELTA..sup.9,11 steroid via an elimination reaction. However, the prior art methods are not regiospecific in the case of 11.alpha.-hydroxy steroids and typically lead to mixtures of .DELTA..sup.9,11 steroid containing 10-15% of the analogous .DELTA..sup.11,12 steroids. Separation of these regio-isomeric products is difficult, generally requiring laborious physical separation procedures, resulting in increased costs and lower yields. It would therefore be desirable to develop an efficient regioselective method for preparing .DELTA..sup.9,11 steroids, from either 11.alpha.- or 11.beta.-hydroxy steroids, for use as intermediates in the synthesis of corticosteroids.
The introduction of a 21-chloro group is also of commercial importance, e.g. for preparing intermediates and therapeutically important compounds such as mometasone. The conversion of 21-hydroxy steroids to the analogous 21-chloro steroid by chloride displacement of a 21-methanesulfonyl intermediate is known. However, this reaction is not regioselective in the case of 11-hydroxy steroids, as methanesulfonyl chloride reacts with both the 11- and 21-hydroxy groups. In addition, Wuts, et al., Syn. Comm., 23, (15) 2199-2211 (1993) describes a method for preparing 21-chloro steroids using the Vilsmeier reagent (prepared from DMF and POCl.sub.3 or phosgene).
In view of the importance of beth 21-chloro groups and 9,11-double bends it would be desirable to develop a one-step process for efficiently introducing both functional groups in a single steroid molecule